This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study seeks to find a way to decrease frequency and severity of COPD exacerbations, illnesses that often lead to hospitalizations and death and are the largest component of COPD health care expenditures. Previous studies have shown that a variety of antibiotics, the macrolides, given chronically, reduce exacerbations in both bronchietasis and cystic fibrosis (two other lung diseases). It is this study?s purpose to see if chronic administration of the macrolide antibiotic Azithromycin (Zithromax) will reduce COPD exacerbations;the study is powered to detect a 20% reduction if one exists. Azithromycin was chosen because of its excellent side effect profile, its anti-inflammatory as well as antibiotic effects and because it will soon be off patent and will (if the study is successful) provide a relatively low-cost enhancement to COPD therapy The Network will recruit 1130 patients (approximately 113 at this site) with COPD and a high risk of exacerbation (marked by previous exacerbation or chronic supplemental oxygen use) for a one-year trial. Participants will be randomized in a double-blind manner to either Azithromycin 250mg daily or an identically-appearing placebo. The drug will be dispensed in a high-technology blister pack card;a computer chip imbedded in the blister pack will allow tracking when the medicine is taken each day. Participants will come to the study center on 8 occasions (for roughly 3 hours/visit): two in the initial evaluation period, at months 1, 3, 6, 9 and 12 of the intervention and one month following the end of the intervention. Patients will also receive phone calls to ascertain their health status periodically during the intervention and for the two years (every 6 months) after the intervention ends.